Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
  • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention relates to benzoylguanidines of the formula I ##STR3## in which: R(1), R(2), R(3) are hydrogen, F, Cl, Br, I or (C 1 -C 12 )-alkyl,
• one of the substituents R(1), R(2) or R(3) is N 3 , CN, OH or (C 1 -C 10 )-alkyloxy, if at least one of the remaining substituents R(1), R(2) or R(3) is a sufficiently lipophilic alkyl radical having 3 to 12 carbon atoms,
• R(1), R(2) or R(3) is R(4)--C n H 2n --O m
• n zero or 1
• n zero, 1, 2 or 3,
• R(4) is C p F 2p+1
• R(4) is (C 3 -C 12 )-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl, the aromatic and heteroaromatic ring systems being unsubstituted or substituted by a substituent selected from the group comprising F, Cl, CF 3 , methyl, methoxy or NR(5)R(6), where R(5) and R(6) are hydrogen or (C 1 -C 4 )-alkyl,
• phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group comprising F, Cl, CF 3 , methyl, methoxy, hydroxyl, amino, methylamino or dimethylamino,
• R(6) is hydrogen or methyl
• R(4) is pyridyl, quinolyl or isoquinolyl, m and n must not simultaneously be zero, and with the exception of the compounds benzoylguanidine, 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine, and 3- or 4-methylbenzoylguanidine.
• Preferred compounds are those in which
• R(1), R(2), R(3) are hydrogen, F, Cl, Br or (C 1 -C 8 )-alkyl
• one of the substituents R(1), R(2) or R(3) is OH or (C 1 -C 6 )-alkyloxy, if at least one of the remaining substituents R(1), R(2) or R(3) is a sufficiently lipophilic alkyl radical having 3 to 6 carbon atoms,
• R(1), R(2) or R(3) is R(4)--C n H 2n --O m
• n zero or 1
• n zero, 1, 2 or 3,
• R(4) is C p F 2p+1
• R(4) is (C 5 -C 7 )-cycloalkyl, phenyl, pyridyl, quinolyl or isoquinolyl, the aromatic and heteroaromatic ring systems being unsubstituted or substituted by a substituent selected from the group comprising
• R(5) is phenyl or (C 1 -C 4 )-alkyl
• R(4) is pyridyl, quinolyl or isoquinolyl, m and n must not simultaneously be zero, and with the exception of the compounds benzoylguanidine, 4-chlorobenzoylguanidine, 3,4-dichlorobenzoylguanidine and 3- or 4-methylbenzoylguanidine.
• 3-trifluoromethylbenzoylguanidine hydrochloride 3,5-bistrifluoromethylbenzoylguanidine hydrochloride, 3-methyl-5-trifluoromethylbenzoylguanidine hydrochloride, 4-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride, 4-(4-fluorophenoxy)-3-trifluoromethylbenzoylguanidine hydrochloride, 5-fluoro-3-trifluoromethylbenzoylguanidine hydrochloride, 3-chloro-4-isopropylbenzoylguanidine hydrochloride, 4-tert-butyl-3-methoxybenzoylguanidine hydrochloride, 3-tert-butyl-4-hydroxybenzoylguanidine hydrochloride, 3-tert-butyl-4-isopropylbenzoylguanidine hydrochloride and the pharmacologically acceptable salts thereof.
• the invention also embraces S- and R-configurated compounds.
• the compounds can be in the form of optical isomers, diastereomers, racemates or mixtures of these.
• alkyl radicals mentioned can be either straight-chain or branched.
• (C 1 -C 9 )-heteroaryl is to be understood as meaning, in particular radicals which are derived from phenyl or naphthyl and in which one or more CH groups are replaced by nitrogen and/or in which at least two adjacent CH groups (on the formation of a five-membered aromatic ring) are replaced by S, NH or O.
• one or both atoms of the condensation site of bicyclic radicals such as in indolizinyl
• Heteroaryl is, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
• the invention furthermore relates to a process for the preparation of a compound I, which comprises reacting a compound of the formula II ##STR4## in which R(1) to R(3) have the abovementioned meaning and L is a leaving group which can readily be substituted by a nucleophile, with guanidine.
• An activated carboxylic acid derivative of the formula I is reacted with guanidine in a manner known per se, in a protic or aprotic polar, but inert, organic solvent.
• aprotic inert solvents such as THF, dimethoxyethane or dioxane.
• a base such as, for example, NaOH is used as solvent, water can also be used in the reaction of II and III.
• the process is carried out advantageously with the addition of an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid.
• an acid scavenger for example in the form of excess guanidine
• nucleophilic reagents such as phenols or alcohols
• R(4)--C n H 2n --OH or their alkali metal salts giving the corresponding benzoic acid derivatives.
• nitro groups can be reduced to the corresponding aminobenzoic acid by means of Sandmeyer or Ullmann reactions and then lead to the desired, in particular halogen-substituted, benzoic acid derivatives.
• chlorine, bromine or iodine can also be introduced into a particular benzoic acid in a manner known per se by direct halogenation using a Friedel-Crafts catalyst.
• benzoylguanidines I are weak bases and can bind acid with the formation of salts.
• Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
• the compounds I are substituted acylguanidines.
• the best known representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic.
• German Offenlegungsschrift 3,502,629 discloses benzoylguanidines which are substituted in the m-position with a phenoxy group and which always have at least two substituents in the phenoxy group. These compounds are used in crop protection.
• U.S. Pat. No. 3,780,027 claims acylguanidines which are similar to the compounds of the formula I with regard to the structure and which are derived from commercially available loop diuretics, such as bumetanide. Accordingly, powerful salidiuretic activity is reported for these compounds.
• the compounds according to the invention have no undesired and disadvantageous salidiuretic, but very good antiarrhythmic, properties, such as, for example, in the case of oxygen deficiency symptoms. Due to their pharmacological properties, the compounds are outstandingly suitable for use as antiarrhythmic pharmaceuticals with a cardioprotective component for the prophylaxis and treatment of infarctions and for the treatment of angina pectoris, and they also preventively inhibit, or greatly reduce, the pathophysiological processes involved in ischemically induced damage, in particular when ischemically induced cardiac arrhythmias are triggered.
• the compounds of the formula I according to the invention can be used, due to inhibition of the cellular Na + /H + exchange mechanism, as pharmaceuticals for the treatment of all acute or chronic, ischemia-triggered types of damage or diseases which are primarily or secondarily induced thereby.
• the compounds are also valuable protective pharmaceuticals for carrying out invasive angioplastic treatment, for example on the heart or on peripheral blood vessels. Due to their protective activity against ischemically induced types of damage, the compounds are also suitable for use as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of apoplexy or of cerebral edema. Moreover, the compounds of the formula I according to the invention are also suitable for the treatment of forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock.
• the compounds of the formula I according to the invention are distinguished by powerful inhibitory action on cell proliferations, for example fibroblast cell proliferation and proliferation of the smooth vascular muscle cells. This is why the compounds of the formula I are suitable as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, and they can therefore be used as antiatherosclerotics, agents against late complications in diabetes, cancers, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophias and hyperplasias, in particular in prostatic hyperplasia or prostatic hypertrophia.
• the compounds according to the invention are valuable inhibitors of the cellular sodium proton antiporter (Na + /H + exchanger), which is elevated in a large number of diseases (essential hypertension, atherosclerosis, diabetes and the like) even in those cells which are readily accessible to measurements, such as in erythrocytes, thrombocytes or leukocytes.
• the compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostics for determining, and distinguishing between certain forms of hypertension, but also of atherosclerosis, diabetes, proliferative diseases, and the like.
• the compounds of formula I are suitable for preventive therapy for preventing the genesis of hypertension, such as of essential hypertension.
• the compounds are distinguished by an inhibition of the hydrochloric acid production of the parietal cells of the stomach, and they can therefore be used as pharmaceuticals for the treatment of gastrointestinal diseases.
• gastrointestinal disorders and diseases of the esophagus are, for example, gastric and intestinal ulcers and reflux esophagitis.
• compositions which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhaling, the preferred way of administration being dependent on the particular symptom of the disease.
• the compounds I can be used by themselves or together with pharmaceutical auxiliaries, and they can be employed both in veterinary medicine and human medicine.
• auxiliaries are suitable for the desired pharmaceutical formulation.
• auxiliaries which can be used in addition to solvents, gel-formers, bases for suppositories, tableting auxiliaries, and other excipients for active substances are, for example, antioxidants, dispersants, emulsifiers, antifoamers, flavor improvers, preservatives, solubilizers or colorants.
• the active compounds together with the additives suitable for this purpose are mixed and formulated by customary methods to give suitable dosage forms, such as tablets, sugar-coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions.
• suitable dosage forms such as tablets, sugar-coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions.
• Inert excipients which may be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular maize starch. Dry granules or moist granules can be used for the preparation.
• oily excipients or examples of solvents are vegetable or animal oils, such as sunflower oil or codliver oil.
• the active compounds for subcutaneous or intravenous administration, the active compounds, if desired together with the substances which are customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, are dissolved, suspended or emulsified.
• suitable solvents are: water, physiological saline, or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions, such as glucose or mannitol solutions, or else a mixture of the various solvents which have been mentioned above.
• compositions which are suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or else in a mixture of such solvents.
• a pharmaceutically acceptable solvent such as, in particular, ethanol or water, or else in a mixture of such solvents.
• the formulation can also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, and a propellant gas.
• concentration of active substances in such a preparation is generally from about 0.1 to 10, in particular from about 0.3 to 3, % by weight.
• the dose of the active substance of the formula I to be administered and the frequency of the administration will depend on the potency and duration of action of the compounds used; in addition also on the nature and severity of the disease to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
• the daily dosage rate of a compound of the formula I in the case of a patient of approximately 75 kg will be at least 0.001 mg/kg, preferably 0.01 mg/kg, up to not more than 10 mg/kg, preferably 1 mg/kg, of body weight. If the disease is acute, such as immediately after suffering a cardiac infarction, even higher, and in particular, more frequent, doses may also be required, for example up to 4 single doses per day. Up to 200 mg per day may be required, in particular for intravenous administration, such as in the case of a patient who has suffered an infarction and is under intensive care.
• 3,5-Dichloro-4-(4-chlorobenzyloxy)benzoic acid was obtained by reacting 3,5-dichloro-4-hydroxybenzoic acid with 4-chlorobenzyl chloride in DMF in the presence of potassium carbonate at 40° C., followed by hydrolysis of the 4-chlorobenzyl 3,5-dichloro-4-(4-chlorobenzyloxy) benzoate in aqueous/methanolic solution with NaOH and subsequent acidification using 2N HCl, m.p. 215°-220° C.
• 4-tert-Butylbenzoylguanidine is obtained by treating the corresponding hydrochloride of Example 19 with triethylamine in dimethylformamide and water. Colorless, crystalline substance, m.p. 255°-258° C.
• 3,5-Dibromobenzoylguanidine hydrochloride is obtained from 3,5-dibromobenzoylguanidine (Example 28) by treatment with methanolic hydrochloric acid. Colorless crystals, m.p. 275° C.
• 3-Azido-5-trifluoromethylbenzoylguanidine hydrochloride is obtained from 3-azido-5-trifluoromethylbenzoic acid following the general protocol (m.p. 123°-125° C.), which is prepared from 3-amino-5-trifluoromethylbenzoic acid and sodium azide by diazotization and then by Sandmeyer reaction. Colorless, crystalline compound. m.p. 197° C.
• 4-Bromo-3-methylbenzoylguanidine hydrochloride is obtained from 4-bromo-3-methylbenzoic acid following the general protocol. Colorless crystals. m.p. 250° C.
• 3-Chloro-4-fluorobenzoylguanidine hydrochloride is obtained from 3-chloro-4-fluorobenzoic acid following the general protocol. Colorless crystals. m.p. 188°-189° C.
• 3,5-Di-tert-butylbenzoylguanidine hydrochloride is obtained from 3,5-di-tert-butylbenzoic acid following the general protocol. Colorless crystals. m.p. 180° C.
• 3-Bromo-5-chlorobenzoylguanidine hydrochloride is obtained from 3-bromo-5-chlorobenzoic acid following the general protocol. Colorless crystals. m.p. 268° C.
• 3-Bromo-4-methylbenzoylguanidine hydrochloride is obtained from 3-bromo-4-methylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 250° C.
• 3-Chloro-4-isopropylbenzoylguanidine hydrochloride is obtained from 3-chloro-4-isopropylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 185° C.
• 3,4,5-Trichlorobenzoylguanidine hydrochloride is obtained from 3,4,5-trichlorobenzoic acid analogously to the general protocol. Colorless crystals. m.p. 194° C.
• 3-Bromo-5-methylbenzoylguanidine hydrochloride is obtained from 3-bromo-5-methylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 235°-236° C.
• 4-Chloro-3,5-dimethylbenzoylguanidine hydrochloride is obtained from 4-chloro-3,5-dimethylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 244°-247° C.
• 3-Trifluoromethyloxybenzoylguanidine hydrochloride is obtained from 3-trifluoromethyloxybenzoic acid analogously to the general protocol. Crystals. m.p. 146°-148° C.
• 4-Trifluoromethyloxybenzoylguanidine hydrochloride is obtained from 4-trifluoromethyloxybenzoic acid analogously to the general protocol. Crystals. m.p. 259° C.
• 4-Cyclohexylbenzoylguanidine hydrochloride is obtained from 4-cyclohexylbenzoic acid analogously to the general protocol. Crystals. m.p. 273° C.
• 3-Chloro-4-cyclopentyloxybenzoylguanidine hydrochloride is obtained from 3 -chloro-4-cyclopentyloxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 273° C.
• 3-Chloro-4-cyclopentyloxybenzoic acid of m.p. 148°-151° C., is obtained by hydrolysis of methyl 3-chloro-4-cyclopentyloxybenzoate (amorphous oily substance) in a mixture of aqueous NaOH and dioxane followed by acidification of the alkaline hydrolysis solution using half-concentrated hydrochloric acid.
• Methyl 3-chloro-4-cyclopentyloxybenzoate is obtained by boiling methyl 3-chloro-4-hydroxybenzoate and iodocyclopentane in acetone in the presence an excess of solid, ground potassium carbonate. After the acetone has been evaporated, the oily residue is taken up in water, the mixture is subsequently extracted using ethyl acetate, the extract is dried over sodium sulfate, and the solvent is then evaporated.
• 3-Isopropyl-4-methoxybenzoylguanidine hydrochloride is obtained from 3-isopropyl-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 214° C.
• 3-Chloro-4-cyclooctyloxybenzoylguanidine hydrochloride is obtained from 3-chloro-4-cyclooctyloxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 243° C.
• 3-Chloro-4-cyclooctyloxybenzoic acid of m.p. 110°-112° C., is obtained by hydrolysis of methyl 3-chloro-4-cyclooctyloxybenzoate (amorphous oily substance) in a mixture of aqueous NaOH and methanol, followed by acidification of the alkaline hydrolysis solution with half-concentrated hydrochloric acid.
• Methyl 3-chloro-4-cyclooctyloxybenzoate is obtained by heating methyl 3-chloro-4-hydroxybenzoate and cyclooctyl bromide in dimethylformamide for 20 hours in the presence of an excess of solid, ground potassium carbonate. After the solvent has been evaporated, the oily residue is taken up in water, the mixture is subsequently extracted using ethyl acetate, the extract is dried over sodium sulfate, and the solvent is then evaporated.
• 4-tert-Butyl-3-methoxybenzoylguanidine hydrochloride is obtained from 4-tert-butyl-3-methoxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 227°-231° C.
• the 4-tert-Butyl-3-methoxybenzoic acid used is obtained by oxidation of 4-tert-butyl-3-methoxytoluene in an aqueous/alkaline solution of potassium permanganate.
• 3-Bromo-4-fluorobenzoylguanidine hydrochloride is obtained from 3-bromo-4-fluorobenzoic acid analogously to the general protocol. Colorless crystals. m.p. 215° C.
• 3-tert-Butyl-4-hydroxybenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-hydroxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 216° C.
• 3-Cyano-4-methoxybenzoylguanidine hydrochloride is obtained from 3-cyano-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 236° C.
• 3-tert-Butyl-4-methoxybenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-methoxybenzoic acid analogously to the general protocol. Colorless crystals. m.p. 260°-62° C.
• 3-Chloro-4-(1-hexyl)benzoylguanidine hydrochloride is obtained from 3-chloro-4-(1-hexyl)benzoic acid analogously to the general protocol. Colorless crystals. m.p. 286° C. (decomposition).
• 3-tert-Butyl-4-(2-methyl-1-propyl)benzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-(2-methyl-1-propyl)benzoic acid analogously to the general protocol. Colorless crystals.
• 4-Isopropyl-3-pentafluoroethylbenzoylguanidine hydrochloride is obtained from 4-isopropyl-3-pentafluoroethylbenzoic acid analogously to the general protocol. Colorless, amorphous solid.
• 3-tert-Butyl-4-isopropylbenzoylguanidine hydrochloride is obtained from 3-tert-butyl-4-isopropylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 145°-165° C.
• 4-Isopropylbenzoylguanidine hydrochloride is obtained from isopropylbenzoic acid analogously to the general protocol. Colorless crystals. m.p. 193°-198° C.
• 3-Trifluoromethylbenzoylguanidine is obtained from 3-trifluorobenzoic acid analogously to the general protocol. Colorless, amorphous-oily composition.
• 3-Trifluoromethylbenzoylguanidine methanesulfonate is obtained analogously to the general protocol from 3-trifluoromethylbenzoylguanidine by treating the latter with methanesulfonic acid in ethyl acetate. Colorless crystals. m.p. 167°-170° C.
• 4-Fluoro-3-isobutylbenzoylguanidine hydrochloride is obtained from 4-fluoro-3-isobutylbenzoylguanidine analogously to the general protocol. m.p. 136°-140° C.

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• 1994
  • 1994-02-16 ES ES94102322T patent/ES2107698T3/es not_active Expired - Lifetime
  • 1994-02-16 EP EP94102322A patent/EP0612723B1/de not_active Expired - Lifetime
  • 1994-02-16 AT AT94102322T patent/ATE157351T1/de not_active IP Right Cessation
  • 1994-02-16 DE DE59403818T patent/DE59403818D1/de not_active Expired - Lifetime
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• 1996
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